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What information is available regarding use of anticoagulation in the management of COVID-19?

Introduction

The coronavirus disease of 2019 (COVID-19) is a newly emergent viral respiratory infection now deemed a pandemic by the World Health Organization (WHO).1,2 Most patients with COVID-19 will develop mild illness, but approximately 14% experience severe disease requiring hospitalization. It is well accepted that patients with severe COVID-19 may develop complications such as acute respiratory distress syndrome (ARDS), sepsis and septic shock, and kidney and cardiac injury.2

Experience with COVID-19 has demonstrated the ability of the virus to affect various organ systems and cause numerous serious adverse clinical outcomes. In the rapidly evolving literature base of COVID-19, a new area of research relates to the effects of the virus on hematologic and coagulation parameters and the risk of thrombosis. A number of recent publications have reported on the suspected mechanisms of coagulopathy associated with COVID-19, and emerging research is beginning to describe the potential efficacy of anticoagulation in management of COVID-19. This review describes current knowledge of anticoagulation in management of COVID-19, with a focus on currently available studies and recommendations from professional societies.

COVID-19—associated coagulopathy

Early reports of characteristics of patients with COVID-19 demonstrated abnormal coagulation parameters.3 Findings from the first 99 hospitalized patients in Wuhan, China described elevations in prothrombin time (PT), activated partial thromboplastin time (aPTT), and D-dimer in 5%, 6%, and 36% of patients, respectively.4 Accruing data suggest that aPTT and PT undergo less drastic changes, and other presentations are more common. These include thrombocytopenia, elevated D-dimer, lymphopenia, and elevated fibrinogen, which have been reported in 36.2%, 46.4%, 80%, and 97% of cases, respectively.3,5,6 The utility of D-dimer as a prognostic variable for COVID-19 has received particular attention, and elevations ranging from 500 to 1000 ng/mL have been associated with increased mortality.3,7-12 Because of these characteristic coagulopathic changes, some are referring to this syndrome as COVID-19—associated coagulopathy (CAC). 3

Thrombotic complications may occur in CAC. Reported incidence of venous thromboembolism (VTE) in current publications describing patients with COVID-19 ranges from 1.1% in hospitalized patients in non-ICU wards to 69% in patients screened with lower extremity ultrasound.13 Unique characteristics of COVID-19 appear to increase the risk of thrombotic events, as reported in a multicenter prospective cohort study of French intensive care unit (ICU) patients with acute respiratory distress syndrome (ARDS).14 Those with COVID-19 ARDS experienced significantly more thrombotic events compared with propensity score-matched historical controls with non-COVID-19 ARDS (11.7% vs 4.8%; odds ratio, 2.6; 95% confidence interval, 1.1 to 6.1). Overall, while the incidence of thrombosis in patients with COVID-19 remains poorly defined, a general consensus is developing that there is a clinically meaningful risk of thrombosis.

Pathophysiologic mechanisms have been proposed to explain the link between COVID-19, CAC, and thrombosis. The COVID-19 virus may cause endothelial dysfunction, systemic inflammation, and hypoxemia, all of which have been associated with thrombus formation.15,16 Moreover, hospitalized patients who are immobile during bedrest are at increased risk for thrombosis.17,18

Given these emerging data, there is rationale for consideration of systemic anticoagulation in patients with COVID-19.19 Heparin in particular may have additional benefits because it has been shown to bind to COVID-19 spike proteins, potentially inhibiting viral cell entry, and to downregulate interleukin-6, which is elevated in patients with COVID-19 and is a biomarker of inflammation.17

Current evidence

To date, the evidence base for use of anticoagulation in management of COVID-19 includes only several observational studies; comparative studies are summarized in Table 1. Generally, these findings preliminarily indicate that anticoagulation may offer significant therapeutic benefit, though this may be limited only to patients with severe disease. This is demonstrated in multiple studies that found mortality was not different between groups in overall comparisons of the entire patient cohort, but was significantly improved with anticoagulation in subgroups of patients with severe disease (defined variably as sepsis-induced coagulopathy score ≥ 4, D-dimer levels > 6 times upper limit of normal, and requirement of mechanical ventilation).

Table. Comparative retrospective cohort studies of anticoagulation in COVID-19. 20-23
Study and designComparator armsResults
(overall cohort)		Results
(subgroups)
Ayerbe23

Retrospective cohort of patients with COVID-19 in 17 hospitals in Spain		Heparin (n=1734)

No heparin (n=285)		Mortality
Heparin was associated with lower mortality in fully adjusted model (OR, 0.42; 0.26 to 0.66)a		Not performed
Llitjos20

Retrospective cohort of patients with severe COVID-19 in France		Prophylactic AC (n=8)

Therapeutic AC (n=18)

Doses not reported		VTE
100% vs 56% with prophylactic vs therapeutic AC (p=0.03)		Not performed
Tang 21

Retrospective cohort of patients with severe COVID-19 in Wuhan, China		Heparin (n=99)

No heparin (n=350)

94 vs 5 patients received LMWH and UFH, respectively		28-day mortality
30.3% vs 29.7% with vs without heparin (p=0.910; OR, 1.647; 95% CI, 0.929 to 2.921)b		SIC score >=4
28-day mortality
40.0% vs 64.2% with vs without heparin (OR, 0.372; 95% CI, 0.154 to 0.901)

D-dimer >6x ULN
28-day mortality
32.8% vs 52.4% with vs without heparin (OR, 0.442; 95% CI, 0.226 to 0.865)
Paranjpe22

Retrospective cohort of patients hospitalized with COVID-19 in New York City		AC (n=786)

No AC (n=1987)

Doses not reported		Median survival
21 vs 14 days with vs without AC (p=NR)

In-hospital mortality
22.5% vs 22.8% with vs without AC (p=NR)

Major bleeding
3.0% vs 1.9% with vs without AC (p=0.2)		Patients requiring MV
Median survival
21 vs 9 days with vs without AC (p=NR)

In-hospital mortality
29.1% vs 62.7% with vs without AC (p=NR)

Longer duration of anticoagulation was associated with reduced mortality risk (adjusted HR, 0.86 per day of treatment; 95% CI, 0.82 to 0.89)c
aModel adjusted for age, gender, oxygen saturation <90%, temperature >37° C, and use of investigational drugs for COVID-19 (hydroxychloroquine, azithromycin, corticosteroids, tocilizumab, lopinavir + ritonavir, oseltamivir).
bModel adjusted for age, sex, ethnicity, body mass index, hypertension, heart failure, atrial fibrillation, diabetes, anticoagulation prior to admission, intubation, and admission date.
cModel adjusted for age, sex, comorbidity, prothrombin time, platelet count, and D-dimer.
Abbreviations: AC=anticoagulation; CI=confidence interval; COVID-19=coronavirus disease of 2019; HR=hazards ratio; LMWH=low-molecular weight heparin; MV=mechanical ventilation; NR=not reported; OR=odds ratio; SIC=sepsis-induced coagulopathy; UFH=unfractionated heparin; ULN=upper limit of normal; VTE=venous thromboembolism.

These findings of current studies of anticoagulation in management of COVID-19 are promising, particularly given the large magnitudes of benefit in the terminal endpoint of mortality and the reproducibility of findings by independent analyses. Nonetheless, these early studies suffer from meaningful limitations.20-22 Confounding by indication is a major concern because of the potentially greater propensity for severely ill patients to selectively be prescribed anticoagulation. Additionally, adjustment for covariates was performed in several studies, but each differed in their inclusion of relevant prognostic variables.20-23 Moreover, the uncontrolled nature of these studies leaves the possibility for variation in anticoagulation regimens, which is apparent by the lack of reported doses and specific anticoagulants used. Lastly, all studies included small sample sizes, which may leave them underpowered to analyze some outcomes and may limit their generalizability. Answers to these lingering questions may come from randomized controlled trials currently registered at clinicaltrials.gov that will investigate various anticoagulation regimens.24-27 However, these studies’ estimated completion dates range between late 2020 and early 2021.

Recommendations

Guidance documents with a focus on antithrombotic management of COVID-19 are available from multiple societies, including the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the US National Institutes of Health, and the World Health Organization.1,12,13,28,29 These guidances recognize the important hematologic and coagulopathic derangements in COVID-19 and the potentially useful role for measurement of these parameters in hospitalized patients.12,28 Specifically, the ISTH recommends monitoring of D-dimer, PT, and platelet count (in decreasing order of importance) in all patients who present with COVID-19.28 However, as indicated in the NIH guideline, there is insufficient data to recommend laboratory testing to guide management decisions at this time.12

Recommended anticoagulants in management of COVID-19 in these guidances currently includes low-molecular weight heparin (LMWH) and unfractionated heparin (UFH).1,12,13,28,29 Though other guidances indicate no preference between these anticoagulants, the WHO and a guidance from multiple international societies, including the ISTH, prefer LMWH.1,2,29 Neither society explicitly states their rationale for this preference, but LMWH may be more appealing because of its ability to be dosed once daily, thus reducing both use of personal protective equipment (PPE) and healthcare worker exposure during administration.1

Use of direct-acting oral anticoagulants (DOACs) is not endorsed by current guidances in hospitalized patients and was not reported in the aforementioned studies.1,12,13,20-22,28 Moreover, LMWH and UFH may be safer in hospitalized critically ill patients because of their shorter duration of action and comparatively fewer drug-drug interactions compared with DOACs.13 However, outpatients with mild COVID-19 who are treated with vitamin K antagonists and have limited access to care may be transitioned to a DOAC in order to avoid the need for periodic monitoring of international normalized ratio. 1,13

Gaps in knowledge

Various aspects of anticoagulation as management of COVID-19 remain unclear. For example, current guidances do not define which patients with COVID-19 are optimal candidates for anticoagulation and there is discordance in current guidelines.1,12,13,28 The ISTH recommend that all patients (including non-critically ill patients) requiring hospital admission for COVID-19 should be considered for anticoagulation with prophylactic dose LMWH if there is no contraindication.28,30 In contrast, the NIH guidance states that VTE prophylaxis in hospitalized adults with COVID-19 should follow standard of care for other hospitalized adults, and reinforces that current research is too limited to influence the standard of care for COVID-19.12

The need for anticoagulation is unclear in patients with mild COVID-19 who are quarantined but have significant comorbidities and risk factors for thrombosis.1 Current recommendations for such patients are simply that they remain active during quarantine. Further research is needed regarding appropriate risk stratification tools; ISTH states that the Caprini, IMPROVE, and Padua models are options, and recommends their prognostic assessments of thrombosis be weighed against the risk of bleeding.

The optimal anticoagulant dose regimen for management of COVID-19 is also uncertain. The ASH state that many institutions have adopted intermediate-intensity dosage regimens (ie, the usual daily LMWH dose administered twice daily); however, there is a lack of published evidence for this.13 Somewhat conflicting this is a guidance prepared by Subcommittees of the ISTH.30 This guidance states that intermediate-dose LMWH can be considered in high-risk patients, and suggests prophylactic doses of LMWH or UFH for routine use. Statements from ASH and ISTH are in agreement that until further information is available, therapeutic-intensity anticoagulation should not be used, including in severely ill patients with COVID-19 who do not have confirmed or suspected VTE.13,30

Lastly, extended thromboprophylaxis in patients discharged after COVID-19—related hospitalization is not currently recommended as routine practice given current knowledge.1,12 The guidance from the ISTH Subcommittees states that extended thromboprophylaxis can be considered, particularly in patients with high VTE risk, though committee members varied in their recommendations. Only 70% recommended post-discharge thromboprophylaxis, and responses regarding the recommended duration ranged from 0-14 to 14-30 days.30 Decisions on extended thromboprophylaxis should be individualized based on risks of thrombosis and bleeding, and should consider either LMWH or Food and Drug Administration-approved regimens (eg, betrixaban and rivaroxaban).

Conclusion

The best currently available evidence regarding anticoagulation as management for COVID-19 is limited to several studies that suggest anticoagulation may improve mortality, though this benefit may only occur in patients with severe disease. These studies suffer from important limitations that preclude their use as supporting evidence for routine anticoagulation in all patients with COVID-19. Questions remain regarding the optimal anticoagulant regimen and patients who are the most appropriate candidates; currently registered RCTs will hopefully provide further clarity beginning in late 2020. For now, LMWH and UFH are endorsed by various guidance documents from professional societies, with some favoring LMWH. As with many other aspects of COVID‑19, there will be continued rapid publication of new research as well as revision of current recommendations that will update our understanding of anticoagulant management in COVID‑19. Clinicians should remain vigilant to appropriately adopt these changes into practice and to provide optimal anticoagulation in managing patients with COVID-19.

References

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  2. World Health Organization. Clinical management of severe acute respiratory infection when COVID-19 is suspected. World Health Organization. Updated March 13, 2020. Accessed May 19, 2020. https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected
  3. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020. doi:10.1182/blood.2020006000
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  11. Panigada M, Bottino N, Tagliabue P, et al. Hypercoagulability of COVID-19 patients in intensive care unit. a report of thromboelastography findings and other parameters of hemostasis. Accepted manuscript. Published online April 17, 2020. J Thromb Haemost. doi:10.1111/jth.14850
  12. National Institutes of Health. Antithrombotic therapy in patients with COVID-19. National Institutes of Health. Updated May 12, 2020. Accessed May 18, 2020. https://www.covid19treatmentguidelines.nih.gov/antithrombotic-therapy/
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  17. Atallah B, Mallah SI, AlMahmeed W. Anticoagulation in COVID-19. Accepted manuscript. Published online April 30, 2020. Eur Heart J Cardiovasc Pharmacother. doi:10.1093/ehjcvp/pvaa036
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  19. Barrett CD, Moore HB, Yaffe MB, Moore EE. ISTH interim guidance on recognition and management of coagulopathy in COVID-19: a Comment. Accepted manuscript. Published online April 17, 2020. J Thromb Haemost. doi:10.1111/jth.14860
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  23. Ayerbe L, Risco C, Ayis S. The association between treatment with heparin and survival in patients with COVID-19. Accepted manuscript. Published online May 31, 2020. J Thromb Thrombolysis. doi:10.1007/s11239-020-02162-z
  24. A randomized trial of anticoagulation strategies in COVID-19. Clinicaltrials.gov identifier: NCT04359277. Updated May 1, 2020. Accessed May 20, 2020. https://clinicaltrials.gov/ct2/show/NCT04359277?term=anticoagulation covid&draw=2&rank=4
  25. Preventing COVID-19 complications with low- and high-dose anticoagulation (COVID-HEP). Clinicaltrials.gov identifier: NCT04345848. Updated April 30, 2020. Accessed May 20, 2020. https://clinicaltrials.gov/ct2/show/NCT04345848?term=anticoagulation covid&draw=2&rank=1
  26. Safety and efficacy of therapeutic anticoagulation on clinical outcomes in hospitalized patients with COVID-19. Clinicaltrials.gov identifier: NCT04377997. Updated May 7, 2020. Accessed May 20, 2020. https://clinicaltrials.gov/ct2/show/NCT04377997?term=anticoagulation covid&draw=2&rank=3
  27. Intermediate or prophylactic-dose anticoagulation for venous or arterial thromboembolism in severe COVID-19 (IMPROVE). Clinicaltrials.gov identifier: NCT04367831. Updated May 19, 2020. Accessed May 20, 2020. https://clinicaltrials.gov/ct2/show/NCT04367831?term=anticoagulation covid&draw=2&rank=5
  28. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-1026. doi:10.1111/jth.14810
  29. Spyropoulos AC, Levy JH, Ageno W, et al. Scientific and Standardization Committee Communication: Clinical Guidance on the Diagnosis, Prevention and Treatment of Venous Thromboembolism in Hospitalized Patients with COVID-19. J Thromb Haemost. 2020. doi:10.1111/jth.14929
  30. Spyropoulos AC, Ageno W, Barnathan ES. Hospital-based use of thromboprophylaxis in patients with COVID-19. Lancet. 2020;395(10234):e75. doi:10.1016/s0140-6736(20)30926-0

Prepared by:
Ryan Rodriguez, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

June 2020

The information presented is current as of May 31, 2020.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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